HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer.
HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer.
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DOI：
10.1155/2023/9335440
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发表时间：
2023
影响因子：
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通讯作者：
Wang, Yong
中科院分区：
文献类型：
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作者：
Wang, Daojuan;Tang, Xun;Ruan, Jianguo;Zhu, Zhengquan;Wang, Rong;Weng, Yajing;Zhang, Yaling;Wang, Tingyu;Huang, Ying;Wang, Hongwei;Su, Zhenzi;Wu, Xiaoke;Tao, Gaojian;Wang, Yong
顺铂耐药是影响卵巢癌患者生存率的关键因素，但卵巢癌顺铂耐药的主要机制尚不清楚，这阻碍了顺铂治疗的最佳使用。蛆提取物（ME）在中药中与其他药物联合治疗昏迷患者和胃癌患者。在本研究中，我们研究了 ME 是否增强卵巢癌细胞对顺铂的敏感性。两种卵巢癌细胞——A2780/CDDP 和 SKOV3/CDDP——在体外用顺铂和 ME 处理。将稳定表达荧光素酶的SKOV3/CDDP细胞皮下或腹腔注射到BALB/c裸鼠体内建立异种移植模型，随后进行ME/顺铂治疗。在顺铂存在下，ME治疗可有效抑制体内和体外顺铂耐药卵巢癌的生长和转移。 RNA测序数据显示A2780/CDDP细胞中HSP90AB1和IGF1R显着增加。 ME处理显着降低HSP90AB1和IGF1R的表达，从而增加促凋亡蛋白p-p53、BAX和p-H2AX的表达，而抗凋亡蛋白BCL2则观察到相反的效果。在 ME 治疗的情况下，抑制 HSP90 ATP 酶对卵巢癌更有益。反过来，HSP90AB1过表达有效抑制了ME促进SKOV3/CDDP细胞中凋亡蛋白和DNA损伤反应蛋白表达增加的作用。 HSP90AB1 过表达抑制顺铂诱导的细胞凋亡和 DNA 损伤，赋予卵巢癌化疗耐药性。 ME可以通过抑制HSP90AB1/IGF1R相互作用来增强卵巢癌细胞对顺铂毒性的敏感性，这可能成为克服卵巢癌化疗中顺铂耐药的新靶点。
Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells—A2780/CDDP and SKOV3/CDDP—were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.